Essential Oils and Bioactive Components Against Arthritis: a Novel Perspective on Their Therapeutic Potential

plants

Review Essential Oils and Bioactive Components against Arthritis: A Novel Perspective on Their Therapeutic Potential

Mariangela Marrelli * , Valentina Amodeo, Maria Rosaria Perri, Filomena Conforti † and Giancarlo Statti † Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy; [email protected] (V.A.); [email protected] (M.R.P.); ﬁ[email protected] (F.C.); [email protected] (G.S.) * Correspondence: [email protected]; Tel.: +39-0984-493168; Fax: +39-0984-493107 These authors jointly supervised and contributed equally to this work. † Received: 18 August 2020; Accepted: 21 September 2020; Published: 23 September 2020

Abstract: Essential oils (EOs) are known to possess a number of beneficial properties. Their antimicrobial, anti-inflammatory, antioxidant, antidiabetic, and cancer-preventing activities have been extensively reported. Due to their wide use as food preservers and additives, as well as their use in agriculture, perfumes, and make-up products, these complex mixtures of volatile compounds have gained importance from a commercial point of view, not only in the pharmaceutical industry, but also in agronomic, food, cosmetic, and perfume industries. An analysis of the recent scientific literature allowed us to highlight the presence of an increasing number of studies on the potential antiarthritic properties of EOs and their main constituents, which seems to suggest a new interesting potential therapeutic application. The aim of this review is to examine the current knowledge on the beneficial effects of essential oils in the treatment of arthritic diseases, providing an overview of the reports on the in vivo and in vitro effects of EOs. Furthermore, this review critically examines the recent findings on the potential roles of the main components of EOs in the exerted beneficial effects. Obtained negative results are also reported.

Keywords: anti-arthritic; anti-inﬂammatory; essential oils; medicinal plants; rheumatoid arthritis; secondary metabolites; terpenes

1. Introduction Arthritis is one of the most common chronic health problems and a major cause of disability [1]. The term “arthritis” derives from the Greek words “arthron” and “ites”, which mean inflammation of the joint. It can be defined as a chronic, inflammatory, and systemic autoimmune disorder characterized by pain, swelling, and rigidity of the synovial joints [2]. Arthritis includes more than 100 different disorders, with osteoarthritis (OA), rheumatoid arthritis (RA), psoriatic arthritis, gout, and fibromyalgia being the most common types [3]. Osteoarthritis is the most frequent form of arthritis [4]. This degenerative disease is characterized by damage to the articular cartilage of the knee, hip, and others lower extremity joints. The estimated risk for knee OA is approximately 47% in women and 40% in men, and its prevalence is projected to increase because of the ageing of the population and the growing occurrence of obesity [5]. Rheumatoid arthritis is a chronic and systemic inflammatory autoimmune disorder in which joint inflammation leads to cartilage and bone damage, disability, and even to systemic complications and enhanced morbidity and mortality [6]. A number of factors, such as genetic factors, the environment, and autoimmunity,

Plants 2020, 9, 1252; doi:10.3390/plants9101252 www.mdpi.com/journal/plants Plants 2020, 9, 1252 2 of 17 play roles in RA pathogenesis [7]. All these factors induce the activation of the immune system, which cause autoantigen presentation with antigen-specific T and B cells activation and aberrant inflammatory cytokines production, thus leading to synovitis and cartilage and subchondral bone destruction. Extra-articular organs, such as the skin and the cardiovascular system, can also be involved [6]. The pharmacological management of both these major forms of arthritis is mostly symptomatic and is aimed at reducing pain and inflammation. This includes the use of non-steroidal anti-inflammatory drugs (NSAIDs) and oral glucocorticoids. Current treatment modalities for RA are based on the use of disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, hydroxychloroquine, and sulfasalazine. However, these drugs can cause serious side effects, including gastrointestinal complaints, pneumonitis, and liver function abnormalities. More recently, biologic drugs (antibodies or soluble receptors for IL-1, IL-6, and TNF-a) have gained importance in the treatment of OA and RA. These agents are able to reduce inflammation and joint destruction, however besides the higher cost of such new agents, which limits their use, both their long-term side effects and benefits have not yet been fully understood. These drugs are not always effective and severe side effects may occur, such as serious infections and increased risk of cancer. Immunosuppressive and cytotoxic drugs (e.g., leflunomide, azathioprine, cyclosporine, and cyclophosphamide) may be used as well, but these drugs also cause a number of toxic side effects [8,9]. As a consequence, the use of botanicals and nutritional supplements has gained importance, and the number of studies on the potential health benefits of plant extracts in the treatment of arthritis is increasing [10]. The antiarthritic potential of plant species and extracts has been extensively reviewed in the last decade, and a number of papers dealing with such botanicals have been published [11–20]. In contrast, the present review aims to specifically offer an overview of the plant essential oils (EOs) with antiarthritic potential. Essential oils are complex mixtures containing low molecular weight compounds, mainly monoterpenes, sesquiterpenes, and oxygenated derivatives, extracted from aromatic plants [21]. A number of biological properties have been detected for EOs, such as antimicrobial, antioxidant, cancer-preventing, antimutagenic, antidiabetic, and anti-inflammatory properties [22–24]. The analysis of the most recent literature allowed us to identify an increasing number of studies focusing on the in vitro and in vivo antiarthritic properties of essential oils. Overall, these findings give interesting perspectives on the therapeutic use of EOs and their chemical constituents.

2. Methods This search, conducted over a period of 5 months, included references published up until July 2020. The academic search engines Google Scholar, Pubmed, Microsoft Academic, and Scopus were utilized. The keywords “essential oils”, “arthritis”, “antiarthritic”, “anti-rheumatoid arthritic eﬀect”, “terpenes”, and “volatile oil” were searched in the databases. These descriptors were combined by using Boolean operators, e.g., “and”, “+”, allowing for more targeted results. Studies focusing on the antiarthritic potential of essential oils in their whole forms or their single pure active components were included in the research, and both in vitro and in vivo studies were taken into account.

3. Essential Oils with Antiarthritic Potential The purpose of this review is to provide an overview of the studies dealing with the potential beneficial effects of EOs and their phytochemical constituents on arthritic conditions. A total of 31 EOs from different plant species have been reported in the literature to have in vitro or in vivo effectiveness. The investigated EOs that have been proved to have antiarthritic potential belong to a number of plant families (Figure1), mainly Lamiaceae (6 species) and Zingiberaceae (5), followed by Cupressaceae, Cyperaceae, Ericaceae, Myrtaceae, and Pinaceae (2). Plants 2020, 9, 1252 3 of 17 Plants 2020, 9, x FOR PEER REVIEW 3 of 19

Figure 1. Number of plant species whose essential oils (EOs) showed antiarthritic potential for the Figure 1. Number of plant species whose essential oils (EOs) showed antiarthritic potential for the diﬀerent families.different families.

3.1. Aquilaria3.1. agallocha Aquilaria agallochaRoxb. Roxb. Aquilaria agallochaAquilaria agallochaRoxb. Roxb. (Thymelaeaceae), (Thymelaeaceae), commonly commonly known knownas “agarwood”, as “agarwood”, grows wild in the grows wild in Himalayan region and East India, and it is cultivated in India, Bangladesh, Indonesia, and Sri Lanka the Himalayan[25]. Agarwood region and EOs Eastand extracts India, contain andit a iscomplex cultivated mixture in of India,sesquiterpenes Bangladesh, and chromones. Indonesia, and Sri Lanka [25].Depending Agarwood on the EOs extraction and extracts technique, contain fatty acids a and complex phenols mixture have also been of sesquiterpenes identified. A number and chromones. Depending onof biological the extraction properties technique, have been fattyreported acids for th andis species, phenols such have as anti alsooxidant, been antimicrobial, identified. A number of antidiabetic, and antinociceptive properties [26,27]. biological propertiesRahman have and colleagues been reported reported for the this anti-arthtritic species, suchpotential as of antioxidant, A. agallocha Roxb. antimicrobial, heartwood antidiabetic, and antinociceptiveessential oil properties(EO) [28]. In vitro, [26, 27at the]. concentration of 500 µg/mL, this essential oil was demonstrated Rahmanto induce and colleagues56.71% inhibition reported of protein the denaturati anti-arthtriticon. The biological potential potential of A. was agallocha also assessedRoxb. in heartwood vivo, in Freund’s adjuvant-induced arthritic rat model. At doses of 125 mg/kg and 250 mg/kg, A. essential oilagallocha (EO) [ 28EO]. inhibitedIn vitro the, atincrease the concentrationin paw volume, with of maximum 500 µg/mL, inhibition this va essentiallues equal oil to 19.78% was demonstrated to induce 56.71%and 27.88%, inhibition respectively. of protein denaturation. The biological potential was also assessed in vivo, in Freund’s3.2. adjuvant-induced Cedrus deodara (Roxb.) arthriticLoud. rat model. At doses of 125 mg/kg and 250 mg/kg, A. agallocha EO inhibited the increase in paw volume, with maximum inhibition values equal to 19.78% and Cedrus deodara (Roxb.) Loud. (Pinaceae), commonly named deodar, is a large evergreen tree 27.88%, respectively.native to the western Himalayas, traditionally used in Ayurvedic medicine for the treatment of inflammatory diseases, such as arthritis and bronchitis [29,30]. 3.2. Cedrus deodaraShinde(Roxb.) and coworkers Loud. investigated the anti-inflammatory activity of C. deodara wood EO in adjuvant arthritic male albino rats [31]. The oil (50 and 100 mg/kg) was administered orally 5 days Cedrusprior deodara to injection(Roxb.) of Loud.FCA, and (Pinaceae), it was administered commonly until day named 30. C. deodar,deodara wood is a EO large inhibited evergreen the tree native to the westernacute Himalayas, phase of adjuvant-induced traditionally response used (first in Ayurvedic7 days following medicine the injection for of the FCA). treatment Moreover, the of inflammatory EO showed analgesic activity against acetic-acid-induced writhing and hot plate reaction in mice. diseases, such as arthritis and bronchitis [29,30]. Shinde3.3. and Chamaecyparis coworkers obtusa investigated (Siebold & Zucc.) the Endl. anti-inflammatory activity of C. deodara wood EO in adjuvant arthriticSuh maleand colleagues albino tested rats the [31 effe].cts The of EO oil from (50 the and leaves 100 of mg Chamaecyparis/kg) was obtusa administered (Siebold and orally 5 days prior to injectionZucc.) Endl. of FCA, (Cupressaceae) and it was on administeredpain-related behavior until and day pro-inflammatory 30. C. deodara cytokineswood in EO rats inhibited with the acute carrageenan-induced arthritis [32]. The obtained results demonstrated the anti-inflammatory and phase of adjuvant-inducedantinociceptive effects response of this essential (first oil. 7 The days intra-articular following application the injection of C. obtusa of FCA). EO inhibited Moreover, the EO showed analgesicpain-related activity behavior against and the acetic-acid-induced expression of pro-inflammatory writhing cytokines and hotTNF- plateα, IL-1 reactionβ, IL-6, and in mice. COX-2 in inflamed knee joints in rats.

3.3. Chamaecyparis obtusa (Siebold & Zucc.) Endl. 3 Suh and colleagues tested the effects of EO from the leaves of Chamaecyparis obtusa (Siebold and Zucc.) Endl. (Cupressaceae) on pain-related behavior and pro-inflammatory cytokines in rats with carrageenan-induced arthritis [32]. The obtained results demonstrated the anti-inflammatory and antinociceptive effects of this essential oil. The intra-articular application of C. obtusa EO inhibited pain-related behavior and the expression of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and COX-2 in inflamed knee joints in rats.

3.4. Cyperus spp. Biradar and coworkers investigated the in vivo antiarthritic potential of the EOs from two Cyperus species (Cyperaceae) from India, C. esculenthus L. and C. rotondus L. [33]. Samples were tested using Plants 2020, 9, 1252 4 of 17 the formaldehyde-induced arthritis model in Wistar albino rats. EOs were administered at the dose of 500 mg/Kg, and after 10 days of treatment they were able to inhibit paw edema by 75.54% (C. rotondus) and 76.58% (C. esculenthus).

3.5. Gaultheria fragrantissima Wall. Gaultheria fragrantissima Wall. is an evergreen shrub belonging to the Ericaceae family that is widely distributed in the Himalayan region and northeastern India. Its EO has been reported to have antioxidant, antibacterial, insecticidal, and nematicidal activities [34]. Uriah and colleagues evaluated the in vitro biological potential of the EO obtained from the leaves of G. fragrantissima [35]. The antiarthritic activity was evaluated with the egg albumin denaturation method and the protein denaturation method using bovine serum albumin as a protein model. At a concentration of 250 µg/mL, the sample induced 49.86% inhibition of protein denaturation.

3.6. Lagerstroemia speciosa (L.) Pers. Lagerstroemia speciosa (L.) Pers. is a common ornamental tree belonging to the Lythraceae family. The leaves are known to contain triterpenes, tannins, and flavones [36]. L. speciosa has been studied for its beneficial effects towards glucose and lipid metabolism [37]. The in vitro antiarthritic potential of the EOs obtained from fresh and dried leaves of this species was investigated by means of the protein denaturation method, using abumin as a protein model [38]. Samples were tested at concentrations ranging from 50 to 800 µg/mL, which were both able to inhibit protein denaturation.

3.7. Litsea cubeba (Lour.) Pers. Litsea cubeba (Lour.) Pers. (Lauraceae) is a shrub or tree distributed in southeastern Asia. It is well known for the EO that can be extracted from the different parts of the plant, with various compositions and yields. The fruit EO is a major source for citral, which is widely used as an aroma additive in food and cosmetics [39]. The anti-arthritis potential of L. cubeba EO was tested by Zhao and coworkers [40]. Limonene, α-citral, and β-citral were the main components in the investigated essential oil. The antiarthritic potential was verified in vivo in collagen-induced arthritic rats. The treatment with EO caused the reduction of paw swelling and serum inflammatory factor levels.

3.8. Ocimum americanum L. Ocimum americanum L. (Lamiaceae) is an annual plant native to Africa, also named American basil, which is commonly used for its flavor properties [41,42]. The antiarthritic potential of O. americanum L. fresh leaves EO was tested in vivo in mice in an experimental model of zymosan-induced arthritis [43]. The EO was characterized by the presence of linalool, eugenol, 1,8-cineole, and camphor as the major compounds. At doses of 150 and 300 mg/kg, O. americanum EO significantly inhibited leukocyte migration to the articular cavity in the knee joint of zymosan-induced arthritic Balb/c mice. Moreover, at 150 mg/kg the EO was able to reduce paw edema in mice, suggesting a suppression of the release of inflammatory mediators such as PGE2 and COX-2.

3.9. Rhododendron tomentosum Harmaja Rhododendron tomentosum Harmaja (Ericaceae) is a small evergreen shrub that is widely distributed in northern and central Europe, North America, and northern Asia. This species has been widely used in folk medicine against arthrosis, rheumatism, pain, wounds, fever, and cough, even if the internal use of its extracts has become rare due to it containing the toxic sesquiterpenoid ledol [44]. The antiarthritic potential of this species was recently assessed by Jesionek and coworkers [45]. The authors tested the antiproliferative activity of different EOs from R. tomentosum on CD4+ and CD8+ limphocytes, which are involved in the pathogenesis of rheumatoid arthritis. The pro-apoptotic effects on synovia-infiltrating Plants 2020, 9, 1252 5 of 17 limphocytes and monocytes or macrophages, which impact rheumatoid-arthritis-affected joint synovium, were also evaluated. In both experiments promising results were obtained.

3.10. Strobilanthus ixiocephala Benth Agarwal and coworkers reported the in vivo anti-inflammatory and antiarthritic activities of the EO from Strobilanthus ixiocephala Benth. flowering tops [46]. This small straggling shrub is present in India and belongs to the Acanthaceae family [47]. The plant species was collected in Nashik, India, and the EO was mainly constituted by the sesquiterpene alcohols ixiocephol and T-cadinol, the monoterpenoid alcohols isoborneol and α-fenchol, and the sesquiterpene β-caryophyllene. Beside the dose-related anti-inflammatory potential demonstrated in both acute and chronic models of inflammation, carragenan-induced rat paw edema, and cotton pellet granuloma, S. ixiocephala EO was effective in Freund’s adjuvant-induced arthritis in rats. At the oral dose of 1 mL/Kg, it inhibited the rat paw edema by 35.56% after 21 days of treatment. The EO was able to suppress the increased lymphocyte count in arthritic rats and the migration of leucocytes into the inflamed area [46].

3.11. Zingiber officinale Roscoe Ginger (Zingiber officinale Roscoe, Zingiberaceae) is a well-known and widely utilized spice plant. This species has been traditionally used for centuries in Chinese, Ayurvedic, and Tibb-Unani medicines for the treatment of different diseases, including rheumatoid arthritis [48,49]. Initially, the studies concerning the antiarthritic effects of this plant species focused on its main phenolic secondary metabolites, gingerols. A potent antiarthritic effect has been demonstrated for gingerol-containing extracts using the streptococcal cell wall (SCW)-induced arthritis model [50]. Funk and coworkers evaluated the effects of ginger essential oils in female Lewis rats with SCW-induced arthritis [51]. The tested sample consisted of a lipophilic sesquiterpene-containing gingerol-free fraction of a dichloromethane extract of ginger rhizome. When injected at a dose 28 mg/kg/d, it was able to inhibit the chronic phase of arthritis (days 13–28), but no effects were detected on acute joint swelling.

3.12. Other Investigated Essential Oils Zhang and coworkers recently evaluated the antiarthritic potential of Zingiberaceae plant EOs, including Alpinia galanga (L.) Willd., Alpinia oxyphylla Miq., Amomum kravanh Pierre ex Gagnep., and Kaempferia galanga L. [52]. These species were demonstrated to down-regulate the expression levels of COX-2, TNF-α, IL-6, and IL-1 in Freund’s adjuvant-induced arthritic rats, with K. galanga being the most eﬀective one.

3.13. Ointment Containing a Mixture of Essential Oils Komeh-Nkrumah and coworkers tested the antiarthritic potential of an ointment containing essential oils from 16 species: Calophyllum inophyllum L. (Clusiaceae), Citrus aurantium L. (Rutaceae), Eucalyptus globulus Labill. (Myrtaceae), Eugenia caryophyllata L. (Myrtaceae), Foeniculum vulgare L. (Apiaceae), Helichrysum angustifolium DC. (Asteraceae), Juniperus virginiana L. (Cupressaceae), Lavandula angustifolia Mill. (Lamiaceae), Myristica fragrans Houtt. (Myristicaceae), Ocimum basilicum L. (Lamiaceae), Pinus sylvestris L. (Pinaceae), Piper nigrum L. (Piperaceae), Rosmarinus officinalis L. (Lamiaceae), Salvia sclarea L. (Lamiaceae), Salvia officinalis L. (Lamiaceae), and Zingiber officinale Roscoe [53]. EOs were used in different percentages, and were combined with corn oil as a carrier oil, as well as with bees wax. This ointment containing 20% EO was applied topically twice daily to Lewis rats to evaluate the effects on adjuvant arthritis, which was induced by injecting M. tuberculosis (Mtb). It was observed that arthritic rats treated with the EO mixture developed less severe clinical arthritis compared to the control group. Moreover, the treatment was able to significantly reduce the levels of TNF-α and IL-1β, as well as the activity of matrix metalloproteinases (MMPs) in the synovial fluid (SF) and synovium-infiltrating cell (SIC) lysate. Studies on the antiarthritic activity of EOs reported in this review are summarized in Table1. Plants 2020, 9, 1252 6 of 17

Table 1. Essential oils investigated for their antiarthritic potential.

Plant Species Common Name Family Part Study Animal Model/In Vitro Test Ref. Alpinia galanga (L.) Willd. greater galangal Zingiberaceae n.s. 1 In vivo Freund’s adjuvant-induced arthritic rats [52] Alpinia oxyphylla Miq. black cardamom Zingiberaceae n.s. In vivo Freund’s adjuvant-induced arthritic rats [52] Amomum kravanh Pierre ex Gagnep. cardamom Zingiberaceae n.s. In vivo Freund’s adjuvant-induced arthritic rats [52] Aquilaria agallocha Roxb. agarwood Thymelaeaceae Heartwood In vitro BSA denaturation method [28] In vivo Freund’s adjuvant-induced arthritic rats Mixture of essential oils tested on adjuvant Calophyllum inophyllum L. Alexandrian laurel Clusiaceae n.s. In vivo [53] arthritis in Lewis rats Cedrus deodara (Roxb.) Loud. deodar Pinaceae Wood In vivo Freund’s adjuvant-induced arthritis in rats [31] Chamaecyparis obtusa (Siebold and hinoki cypress Cupressaceae Leaves In vivo Carrageenan-induced arthritis in rats [32] Zucc.) Endl. Mixture of essential oils tested on adjuvant Citrus aurantium L. bitter orange Rutaceae n.s. In vivo [53] arthritis in Lewis rats Cyperus esculenthus L. yellow nutsedge Cyperaceae n.s. In vivo Formaldehyde-induced arthritis in rats [33] Cyperus rotondus L. yellow nutsedge Cyperaceae n.s. In vivo Formaldehyde-induced arthritis in rats [33] Mixture of essential oils tested on adjuvant Eucalyptus globulus Labill. Tasmanian blue gum Myrtaceae n.s. In vivo [53] arthritis in Lewis rats Mixture of essential oils tested on adjuvant Eugenia caryophyllata L. clove Myrtaceae n.s. In vivo [53] arthritis in Lewis rats Mixture of essential oils tested on adjuvant Foeniculum vulgare L. sweet fennel Apiaceae n.s. In vivo [53] arthritis in Lewis rats Protein denaturation method; Gaultheria fragrantissima Wall. wintergreen Ericaceae Leaves In vitro [35] egg albumin denaturation method Mixture of essential oils tested on adjuvant Helichrysum angustifolium DC. everlasting Asteraceae n.s. In vivo [53] arthritis in Lewis rats Mixture of essential oils tested on adjuvant Juniperus virginiana L. red cedar Cupressaceae n.s. In vivo [53] arthritis in Lewis rats Kaempferia galanga L. kencur Zingiberaceae n.s. In vivo Freund’s adjuvant-induced arthritic rats [52] Lagerstroemia speciosa (L.) Pers. banaba Lythraceae Leaves In vitro Protein denaturation method [38] Plants 2020, 9, 1252 7 of 17

Table 1. Cont.

Plant Species Common Name Family Part Study Animal Model/In Vitro Test Ref. Mixture of essential oils tested on adjuvant Lavandula angustifolia Mill. lavender Lamiaceae n.s. In vivo [53] arthritis in Lewis rats Litsea cubeba (Lour.) Pers. mountain pepper Lauraceae Fruits In vivo Collagen-induced arthritic rats [40] Mixture of essential oils tested on adjuvant Myristica fragrans Houtt. nutmeg Myristicaceae n.s. In vivo [53] arthritis in Lewis rats Ocimum americanum L. American basil Lamiaceae Leaves In vivo Zymosan-induced arthritis in mice [43] Mixture of essential oils tested on adjuvant Ocimum basilicum L. basil Lamiaceae n.s. In vivo [53] arthritis in Lewis rats Mixture of essential oils tested on adjuvant Pinus sylvestris L. Scots pine Pinaceae n.s. In vivo [53] arthritis in Lewis rats Mixture of essential oils tested on adjuvant Piper nigrum L. black pepper Piperaceae n.s. In vivo [53] arthritis in Lewis rats Peripheral blood lymphocytes of healthy volunteers; Rhododendron tomentosum Harmaja marsh Labrador tea Ericaceae shoots In vitro [45] synoviocytes and immune cells isolated from synovia of RA patients Mixture of essential oils tested on adjuvant Rosmarinus officinalis L. rosemary Lamiaceae n.s. In vivo [53] arthritis in Lewis rats Mixture of essential oils tested on adjuvant Salvia sclarea L. clary sage Lamiaceae n.s. In vivo [53] arthritis in Lewis rats Mixture of essential oils tested on adjuvant Salvia officinalis L. sage Lamiaceae n.s. In vivo [53] arthritis in Lewis rats Flowering Strobilanthus ixiocephala Benth. waiti Acanthaceae In vivo Freund’s adjuvant-induced arthritis in rats [46] tops Zingiber officinale Roscoe ginger Zingiberaceae Rhizome In vivo SCW-induced arthritis [51] Mixture of essential oils tested on adjuvant n.s. In vivo [53] arthritis in Lewis rats Note: 1 n.s. not specified. PlantsPlants2020 2020, ,9 9,, 1252 x FOR PEER REVIEW 108 of of 17 19

4.4. EssentialEssential OilsOils MainMain ComponentsComponents withwith PotentialPotential AntiarthriticAntiarthritic ActivityActivity EssentialEssential oils oils are are complex complex mixtures mixtures containing containing low molecular low molecular weight components, weight components, whose extraction whose isextraction above all is carried above out all carried by steam out distillation. by steam distillation. The main chemical The main constituents chemical constituents in EOs include in EOs terpenoids include andterpenoids phenylpropanoids. and phenylpropanoids. Additionally, Additionally, several aromatic several and aromatic aliphatic and compoundsaliphatic compounds are also present. are also Monoterpenes,present. Monoterpenes, sesquiterpenes, sesquiterpenes, and their oxygenated and their oxygenated derivatives arederivatives the major are groups the major of EOs groups chemical of compoundsEOs chemical [21 compounds]. [21]. TheThe antiarthriticantiarthritic potentialpotential ofof terpenes,terpenes, thethe mainmain componentscomponents inin EOs,EOs, hashas beenbeen reviewedreviewed recentlyrecently byby Carvalho Carvalho and and colleagues colleagues [ 54[54].]. AnAnin in vivovivo beneficialbeneficial eeffectffect waswas reportedreported for for 2424 terpenes,terpenes, such such as as thethe triterpenetriterpene emodinol emodinol isolated isolated from fromPaeonia Paeonia emodiemodiWall., Wall., and and the the sesquiterpene sesquiterpene torilin, torilin, which which werewere bothboth demonstrateddemonstrated to to modulate modulate the the levels levels of of pro-inflammatory pro-inflammatory cytokines cytokines TNF- TNF-αα,, IL-1 IL-1ββ,, and and IL-6 IL-6 in in vivo. vivo. EvenEven more more recently, recently, other other interesting interesting terpenes, terpenes, such assuch nerolidol, as nerolidol, were described were described for their beneficial for their ebeneficialffects on arthritic effects on conditions. arthritic conditions. The present The review pres willent focusreview on will these focus further on these terpenes further and terpenes other kinds and ofother EOs kinds components, of EOs components, which were investigatedwhich were investig throughated both throughin vivo bothand inin vitrovivo assays.and in vitro Seven assays. EOs chemicalSeven EOs constituents chemical constituents have been recently have been described recently for described their potential for their antiarthritic potential antiarthritic activity (Figure activity2). (Figure 2).

Figure 2. EO chemical components with antiarthritic potential [55–64]. Figure 2. EO chemical components with antiarthritic potential [55–64]. 4.1. β-Caryophyllene 4.1. β-Caryophyllene β-caryophyllene (Figure2) is a bicyclic sesquiterpene commonly found in a great number of plantβ species,-caryophyllene which is present(Figure in2) essentialis a bicyclic oils fromsesquiterpene various spices, commonly fruits, found and ornamental in a great plantsnumber [65 of]. Thisplant terpene species, is which defined is present as a phytocannabinoid, in essential oils from which various has been spices, approved fruits, and by European ornamental agencies plants and[65]. theThis Food terpene and Drugis defined Administration as a phytocannabinoid, (FDA) as a flavoring which has agent, been food approved additive, by andEuropean taste enhancer agencies [ 66and]. the FoodVijayalaxmi and Drug and Administration colleagues verified (FDA) the as e ffa ectivenessflavoring agent, of this food compound additive, on and FCA-induced taste enhancer arthritic [66]. rats [55Vijayalaxmi]. Paw volume and colleagues and biochemical verified parameters the effectiveness were of evaluated, this compound and β-Caryophyllene on FCA-induced showed arthritic rats [55]. Paw volume and biochemical parameters were evaluated, and β-Caryophyllene showed

10 Plants 2020, 9, 1252 9 of 17 antiarthritic activity. The histopathology and radiology also confirmed the anti-inflammatory activity of this molecule. More recently, El-Sheikh and coworkers assessed the ability of β-caryophyllene to increase the efficacy of methotrexate and leflunomide and to improve their side effects [56]. Experiments were carried out on FCA-induced arthritic rats. The co-administration of β-caryophyllene and methotrexate or leflunomide significantly improved the therapeutic efficacy of these two drugs and also reduced their myelosuppressive and hepatotoxic effects, thus suggesting that β-caryophyllene could be utilized with these two drugs to reduce their side effects or increase their efficacy

4.2. Cinnamaldehyde Cinnamaldehyde (trans-cinnamic aldehyde) is known to be the principal component of cinnamon flavor and a potent antimicrobial compound. It is also detectable in other EOs and is commonly used as a natural food flavorant [67,68]. Different studies underlined the anti-inflammatory activity of this aldehyde, which has been demonstrated to suppress the production of NO, TNF-α, and PGE2 in lipopolysaccharide (LPS)-stimulated macrophages [69]. Cheng and coworkers reported the interesting antiarthritic effects of cinnamaldehyde [57]. At concentrations of 60 and 80 nM, it was able to significantly suppress IL-1β-induced cytokine production in MH7A cells via the suppression of JAK/STAT pathways. Moreover, cinnamaldehyde was demonstrated to have beneficial effects on collagen-induced arthritis in rats. The antiarthritic activity was also evaluated in a rat model of arthritis by Mateen and colleagues [58]. Cinnamaldehyde (10 and 20 mg/kg/day) was administered orally for 15 days in collagen-induced arthritic rats. This compound was able to reduce ROS and NO levels and to increase the reduced glutathione level in arthritic rats. It was able to improve the levels of TNF-α, IL-6, and IL-10. The effectiveness of cinnamaldehyde in decreasing the severity of arthritis was also confirmed by histopathological and radiological findings.

4.3. Eucalyptol The monoterpene oxide eucalyptol (1,8-cineol), the principal component of the essential oils from Eucalyptus leaves [70], is well-known for its anti-inflammatory [71,72] and analgesic properties [73]. Yin and coworkers recently verified the anti-inflammatory and analgesic potential of this compound on a mouse model of gout arthritis [59]. The disease was induced by the injection of MSU crystals into the ankle joint. Eucalyptol was able to reduce MSU-induced allodynia, edema, and neutrophil infiltration in ankle joint tissues. Moreover, this molecule inhibited nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat (LRR)-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation and the production of pro-inflammatory cytokines. The oxidative stress induced by MSU in both RAW 264.7 cells in vitro and in ankle joint tissues in vivo was also reduced.

4.4. Eugenol Eugenol is present in numerous aromatic plants, such as Myristica fragrans Houtt. [74] and Ocimum basilicum L. [75]. The clove plant (Eugenia caryophyllata Thunb.) is the principal source of this compound, representing 45–90% of the total EOs. A wide spectrum of biological properties has been reported for this molecule, including antioxidant, antimicrobial, anti-inflammatory, analgesic, and anticancer activities [76]. The efficacy of this allylbenzene in arthritic rats was verified by Grespan and colleagues [60]. Arthritis was induced in mice through the injection of an emulsion of bovin collagen type II and complete Freund’s adjuvant. Here, 100 µg of eugenol/day were administered orally. This compound was demonstrated to inhibit mononuclear cell infiltration and to decrease the cytokine (TNF-α, IFN-γ, and TGF-β) levels within the ankle joints. Plants 2020, 9, 1252 10 of 17

4.5. Nerolidol Nerolidol is a naturally occurring sesquiterpene alcohol used in cosmetics and as a food-flavoring agent [77,78]. It has been detected in the EOs from more than 30 plant species, such as Ginkgo biloba L. [79], Piper claussenianum (Miq.) C. DC. [80], Momordica charantia L. [81], and Baccharis dracunculifolia DC. [82]. Different biological activities have been described for this terpenoid, such as antioxidant, antifungal, antiparasitic, antinociceptive, anxiolytic, antitumor, and repellent activities [78]. Nano-encapsulated nerolidol was recently studied for its effects on zymosan-induced arthritic mice [61]. An in vivo neutrophil migration assay was performed and both free nerolidol and its polymer nanoparticles pointed out a significant anti-inflammatory activity in arthritic mice, improving the levels of anti-inflammatory cytokines and significantly inhibiting the neutrophil migration into the joint cavity.

4.6. Sclareol Sclareol s a labdane diterpene ditertiary alcohol of high value in the fragrance industry, as this molecule is a good starting material for the semisynthesis of different commercial substances due to its labdane carbon skeleton and the two hydroxyl groups [83]. This terpene is a major component in the EO of clary sage (Salvia sclarea L.) [84], but it is also present in other plant species, such as Cleome spinosa Jacq. [85] and Cistus creticus L. [86]. Sclareol is known to possess anti-inflammatory properties—it has been demonstrated to inhibit NO production and iNOS and COX-2 expression in LPS-stimulated macrophages, and to reduce paw edema and neutrophil infiltration in λ-carrageenan-induced paw edema model [87]. Zhong and colleagues assessed the anti-osteoarthritic properties of sclareol in IL-1β-induced rabbit chondrocytes and in a rabbit model of osteoarthritis induced by ACLT [62]. Sclareol inhibited MMP, iNOS, and COX-2 expression, while increasing the TIMP-1 expression in vitro. It was also able to ameliorate cartilage degradation in vivo. Tsai and coworkers assessed the potential therapeutic effects of sclareol on RA using the human synovial cell line SW982 and the collagen-induced arthritis (CIA) mouse model [63]. The authors demonstrated that this compound can reduce the IL-1β-induced expression of TNF-α, MMP-1, and IL-6 in the SW982 cell line via attenuating NF-κB translocation and the phosphorylation of MAPK pathways. Moreover, it was demonstrated that sclareol (5 and 10 mg/kg intraperitoneally) was able to improve swelling and bone erosions, and a reduction in the number of Th17 cells was also observed.

4.7. Thymoquinone The monoterpene thymoquinone is the major constituent of Nigella sativa L. seeds EO [88]. Antioxidant, anti-inflammatory, antimicrobial, antiparasitic, anticancer, and hypoglycemic activities have been highlighted for this compound [89]. Tekeoglu and coworkers investigated the anti-inflammatory effects of this monoterpene on arthritis in rat model [64]. Arthritis was induced by Freund’s incomplete adjuvant and thytmoquinone was administered orally (2.5 and 5 mg/kg). It was demonstrated that the blockade of pro-inflammatory cytokines, such as TNF-α and IL-1β, reduced the severity of the disease.

5. Mechanisms of Action The in vitro protein denaturation method using bovine serum albumin as a protein model has often been used to assess the antiarthritic potential of some of the EOs reported here, while their anti-inflammatory potential has generally been assessed using a rat ear edema model. The mechanism of action underlying the antiarthritic activity of some of the investigated species reported above was more deeply investigated. In some cases, the different expression levels of pro-inflammatory cytokines and COX-2 in inflamed synovial membranes among control and treated groups were verified. As a results of their investigations, Suh et al. demonstrated that C. obtusa was able Plants 2020, 9, 1252 11 of 17 to inhibit the expression of IL-1β, TNF-α, and IL-6 in the inflamed synovial membrane, as well as IL-1β and IL-6 in an inflamed meniscus [32]. Such effects were also demonstrated for Litsea cubeba, whose EO was able to decrease the TNF-α, IL-1β, IL-6, IL-8, and IL-17A levels and to increase IL-10 in type II collagen-induced arthritic rats [40]. K. galanga and some other species belonging to the Zingiberaceae family also demonstrated impacts on the expression of COX-2, TNF-α, IL-6, and IL-1 in Freund’s adjuvant-induced arthritic rats [52]. The levels of TNF-α and IL-1β and the activity of MMPs in the synovial fluid were also reduced by an ointment containing essential oils from 16 species, among which were E. caryophyllata, C. inophyllum, C. aurantium, and E. globulus, as described by Komeh-Nkrumah and coworkers [53]. Furthermore, Yamada and coworkers [43] demonstrated that oral treatment with O. americanum EO (150 mg/kg) for seven days in arthritic mice was able to inhibit leukocyte migration in the synovial membrane and to attenuate cartilage destruction. Moreover, the treatment significantly reduced IFN-γ levels in synovial tissue. R. tomentosum EO was demonstrated to have antiproliferative and pro-apoptotic activity toward CD4 and CD8 T cells. The same effects were also observed toward synovia-infiltrating monocytes and macrophages [45]. The mechanisms of action of some EOs’ pure components were also investigated. Cinnamaldehyde, for example, has been demonstrated to significantly suppress IL-1β-induced inflammatory cytokine production in human synoviocyte cell line MH7A via the suppression of JAK/STAT pathways [57] and to improve the TNF-α, IL-6, and IL-10 levels in arthritic rats [58]. Eugenol was also demonstrated to decrease the levels of TNF-α, IFN-γ, and TGF-β in induced arthritic rats [60]. Lastly, Tsai and coworkers demonstrated that sclareol can reduce the expression of MMP-1, TNF-α, and IL-6 in SW982 cells via the phosphorylation of MAPK pathways [63].

6. Essential Oils and Their Chemical Components in the Treatment of Arthritis-Related Pain EOs and their chemical components could also be useful in the treatment of arthritis-related pain. Various monoterpenes, sesquiterpenes, and other essential oil constituents have been investigated for their potential antinociceptive activity and have demonstrated interesting analgesic-like activity [90] and different species demonstrated antinociceptive activity in animal models of nociception [91]. For example, M. spicata L. EO and its main constituents, such as menthol, carvone, and limonene, demonstrated analgesic effects in animal models, while spearmint oil was able to reduce pain in osteoarthritis patients [92]. Recently, Mota and colleagues reported the analgesic effect of citral [93], a monoterpene aldehyde identified in the EOs of several plants, such as lemongrass (Cymbopogon citratus (DC.) Stapf.) [94] and ginger (Zingiber officinale Roscoe) [95,96]. It was demonstrated that a single administration of citral (at concentrations of 100 and 300 mg/kg) reversed FCA-induced mechanical allodynia in arthritic rats [93].

7. Negative Results Curcuma longa L. (Zingiberaceae) is known to contain two main classes of secondary metabolites, phenolic curcuminoids, and essential oils, including the major components α-turmerone and β-turmerone. Despite the essential oil from Curcuma longa L. administered via intraperitoneal injection demonstrating a strong antiarthritic effect in female rats with SCW-induced arthritis, significant morbidity and mortality have been observed, which do not support the use of this EO against arthritis [97]. On the contrary, a good antiarthritic effect has been demonstrated in experimental rheumatoid arthritis for curcuminoid-containing turmeric extracts [98], and good antiarthritic potential has been observed for curcumin, the principal curcuminoid of turmeric. Nonose and coworkers demonstrated that this compound was able to reduce the inflammatory response in zymosan-induced arthritis [99]. Plants 2020, 9, 1252 12 of 17

8. Concluding Remarks The low toxicity and reduced genotoxicity are some of the advantages associated with the use of EOs [21]. However, due to the structural relationships within each chemical group, the constituents of EOs may undergo cyclization, isomerization, oxidation, and dehydrogenation reactions, which can easily convert them into each other. As a consequence, the chemical compositions of EOs are influenced not only by factors affecting the plant material, such as the growth stage and habitat, but also by the conditions during both the processing and storage of the plant, during distillation, and during the subsequent handling of thee EOs. Their chemical components are subjected to oxidative damage, chemical transformations, and polymerization reactions that generally lead to sensory and pharmacological properties loss. These deterioration reactions have not been completely addressed and need to be taken into account [100]. Moreover, some old essential oils and oxidized terpenoids have demonstrated skin-sensitizing activity causing contact dermatitis. A study of the toxicity profile of EOs should be carried out, even if this kind of investigation is not simple due to the variability of EO compositions, which in turn may be affected by a number of factors [21,100]. The application of EOs and their constituents in the treatment of arthritis appears to be an interesting new perspective on their potential health benefits. A total of 31 plant EOs and some chemical compounds commonly distributed in different EOs have been reported in the literature to have in vitro or in vivo antiarthritic potential. Many other EOs and components could still be potentially identified. Overall, the analysis of the existent scientific literature focusing on the antiarthritic potential of EOs reveals that the information obtained by in vitro and in vivo studies still needs to be confirmed through clinical investigations.

Author Contributions: Conceptualization and methodology, M.M.; data curation, M.M., V.A. and M.R.P.; writing—original draft preparation, M.M., V.A. and M.R.P.; writing—review and editing, M.M., F.C. and G.S.; supervision, F.C. and G.S. All authors have read and agreed to the published version of the manuscript. Funding: M.M. was supported by a research grant from Piano di Azione e Coesione (PAC) CALABRIA 2014-2020 (Asse prioritario 12, Azione B) 10.5.12, CUP: H28D19000040006. M.R.P. was supported by Programma Operativo Regionale (POR) Calabria FESR/FSE 2014–2020. Conﬂicts of Interest: The authors declare no conﬂict of interest.

Abbreviations

ACLT anterior cruciate ligament transection CIA collagen-induced arthritis COX-2 cyclooxygenase-2 DMARDs disease-modifying antirheumatic drugs EO essential oil FCA Freund’s complete adjuvant FDA Food and Drug Administration IFN-γ interferon-γ IL-1β interleukin-1β IL-6 interleukin-6 iNOS inducible nitric oxide synthase JAK/STAT Janus kinase/signal transducer and activator of transcription LPS lipopolysaccharide MMPs matrix metalloproteinases MSU monosodium urate Mtb M. tuberculosis NLRP3 NOD-, LRR-, and pyrin-domain-containing 3 NO nitric oxide NSAIDs non-steroidal anti-inﬂammatory drugs Plants 2020, 9, 1252 13 of 17

OA osteoarthritis PGE2 prostaglandin E2 RA rheumatoid arthritis SCW streptococcal cell wall SF synovial ﬂuid SIC synovium-inﬁltrating cells SW982 human synovial cell line TGF tumor growth factor TIMPs tissue inhibitors of metalloproteinases TNF-α tumor necrosis factor

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